Different Types of Heart Valves Employ Different Strategies to Stay Alive

Young people have heart valves with a rich blood-vessel supply. Studies in a variety of animal models show that by
maturity, older adults don't normally have blood vessels in their
valves.

Different Types of Heart Valves Employ Different Strategies to Stay Alive

Researchers wanted to know how the valves can survive in
this dynamic environment and get oxygen and nutrients without blood
vessels.

‘Aortic valves under stress tended to prompt angiogenesis, that is accompanied by mineralization and then an osteogenic change. Mitral valves tend to become thick and spongy and more like cartilage, which doesn't have blood vessels in it.’

Rice bioengineers led by Jane Grande-Allen studied physical and
computer models of heart valves to learn how oxygen feeds them and what
happens if they become diseased.

As the valves in a heart stretch with each beat, their cells take in
life-giving oxygen. But if the supply is cut off, aortic and mitral
valves use different strategies to compensate, suggested Rice
University scientists.

The researchers were surprised to find the two distinct types of valves they
studied - the three-leaflet aortic valve between the left ventricle and
the aorta and the two-leaflet mitral valve between the left atrium and
the left ventricle - handle the stress of oxygen starvation differently.

Their results appear this week in the Royal Society journal Interface.

Specifically, Grande-Allen and first author Matthew Sapp wanted to
see how hypoxia - the denial of oxygen to tissues - forced valve cells
and the interstitial matrix that ties them together to react. They used
custom-designed bioreactors to mimic selected conditions in the body and
gradually starved aortic and mitral valve tissues of oxygen over time.

Grande-Allen said, "The heart valves in seniors are quite thick: They get bigger
and the cells are still alive. We want to know how they can survive in
this dynamic environment and get oxygen and nutrients without blood
vessels. We speculated that oxygen is infusing the tissue in vivo,
permeating it as the leaflets move and stretch. This reduces the need
for blood vessels within the leaflets. Now we're starting to look at
that in more detail."

Grande-Allen's ultimate goal is to find new ways to repair or
replace damaged heart valves. Getting there requires a comprehensive
understanding of the complex, layered leaflets, the flaps that direct
blood through the heart. They have to be strong and flexible and resist
compression as they keep blood flowing in the proper direction. But as
they age and especially when they become diseased, they thicken and
become stiff.

These diseases are specific to the type of valve. Aortic valves are
subject to calcific aortic valve disease, characterized by thickening,
stiffening and calcification of the leaflets, leading to stenosis, a
narrowing of exit from the left ventricle.

Mitral valves are at risk of myxomatous degeneration, which leads to
leaflet weakening and valve prolapse, as well as mitral stenosis, which
can be caused by rheumatic fever and is associated with fibrotic
remodeling, collagen accumulation and leaflet stiffening.

To see if hypoxia contributes to disease, the researchers first
modeled oxygen diffusion in healthy valve tissues from pigs and
confirmed previous studies that suggested aortic leaflets need to be in
motion and under pressure for oxygen to spread to cells throughout the
tissue. In testing the valves, they saw that pressure from liquid
thinned and elongated leaflets, which allowed more oxygen to reach
center regions.

In later experiments, they noted that altering the amount of oxygen
available to the leaflets significantly impacted the expression of
markers for hypoxia and angiogenesis (vessel formation) in both types of
valves, but in different ways.

"Aortic valves under stress tended to prompt angiogenesis,"
Grande-Allen said. "That's accompanied by mineralization and then an
osteogenic, or bone-like, change," she said.

"The mitral valve is different. Myxomatous valves tend to become
thick and spongy and more like cartilage, which doesn't have blood
vessels in it. It appears to transform into a tissue that perhaps just
has better oxygen diffusion characteristics."

Mitral valves in hosts with rheumatic fever are far more likely to
add extracellular collagen, making them thicker and oxygen diffusion
more difficult. This prompts blood-vessel growth as cells produce the
hypoxia-induced factor-1 alpha (HIF-1a) protein that induces
angiogenesis. "We believe the normal mitral valve can respond in a way
that allows it to get more oxygen and therefore prevent hypoxia from
occurring," Sapp said.

One important aspect of the project was the creation of a technique
to test the effect of hypoxia on tissues. Sapp built bioreactors that
fed highly controlled amounts of oxygen to the cells.

"Matt is a can-do person," said Grande-Allen, who noted Sapp
recently defended his dissertation. "He built multiple test systems so
we could have very precise measurements of oxygen diffusion through the
valve tissues, some of which confirm what other people have reported and
others that were new.

"Then he translated that data, developed computational models and
built the environmental chambers we used as our incubator to control the
amount of oxygen to the valve tissues," she said. "To have one person
do all of those things was tremendously gratifying. He always came to me
with a solution rather than a problem."

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